Inflammation is a process essential for host defense and tissue repair. However, exuberant defense may cause pathogenic changes leading to vascular diseases such as atherosclerosis. This is because multiple cytokines are involved in the process and each cytokine has multiple effects. For example, TNF signal events use NF?B to promote inflammation and survival whereas activation of the c-Jun N-terminal kinase (JNK) promotes inflammation and apoptosis. We hypothesize that inhibition of JNK without disruption of NF-?B activation provides a valid approach for anti-inflammatory therapy. The cell type that normally limits the inflammatory and atherosclerotic process is the vascular endothelial cell (EC) which can be regulated by proinflammatory (e.g. TNF) and anti-inflammatory mediators (e.g. laminar flow). The major goal of this renewal application is to build from previous two granting periods to characterize novel mediators in JNK regulation. We have identified a unique complex (AIP1 complex) specifically transduces JNK signaling. Our exciting results obtained from AIP1-deficient mice and derived EC generated from our lab support a role of AIP1 in inflammation and ER stress- induced ASK1-JNK activation, and atherosclerosis. We propose the following specific aims: 1). To define the mechanism by which AIP1 activates JNK while inhibits IKK-NF-?B signaling;2) To determine the role of AIP1 in ER stress-induced JNK signaling;3) To determine the role of AIP1 in inflammation and atherosclerosis using animal models. Collectively, these studies should establish the functions of AIP1 for TNF-mediated inflammatory events and flow-mediated protective pathways, and facilitate development of new therapeutic approaches to control atherosclerosis. PUBLIC HEALTH RELEVANCE: Myocardial infarction due to narrowing of arteries manifesting as decreased blood flow remains the leading cause of death in the United States. We will study the effects of a novel scaffolding protein AIP1, on vascular endothelium. Our work may lead to better tests and treatments for atherosclerosis patients.